Addressing the Biology of Health Disparities by Targeting Geographical Ancestry-driven Variants of Immunity

在美国的种族群体中，非洲裔美国人的生活水平仍然最低， 预期和最高总体癌症死亡率（包括结直肠癌、乳腺癌和前列腺癌） 癌症）、婴儿死亡率、哮喘和心脏代谢疾病（包括心脏病， 高血压和肥胖症）。复杂的疾病和环境伤害都引起和/或 通过对治疗剂的个体免疫和可变反应来破坏宿主炎症 部分是由基因变异决定的。个人的精确诊断和治疗 患者反应依赖于在治疗前、治疗期间和/或治疗后评估已知的疾病和免疫标志物。 治疗后本建议将询问功能性影响和药物性不足- 研究了与免疫和药物反应相关的基因变异， 非洲血统（AAs）在AA中最常见的免疫基因变异， 可药用的将被工程化到不同地理血统的细胞系中，并进行评估， 体外和/或体内的功能效应，并通过计算机模拟来预测 野生型蛋白和可能的变体-药物相互作用。筛选化合物的新测定法 将开发具有治疗潜力的药物并用于筛选。先导化合物候选物 然后将在体外和/或体内进行验证、优化和测试。这个项目有潜力 1）建立祖先相关的宿主免疫力作为复杂的生物学参数， 疾病差异; 2）通过确定新的参与者填补关键的知识空白， 炎症机制及其在复杂疾病中的作用;以及，3）可能导致 开发有效的治疗方法，以解决健康差距问题。

Among ethnic groups in the US, African Americans continue to display the lowest life expectancy and highest overall rates of cancer deaths (including colorectal, breast and prostate cancers), infant mortality, asthma, and cardiometabolic diseases (including heart disease, hypertension and obesity). Complex diseases and environmental insults all invoke and/or subvert host inflammation, with individual immune and variable responses to therapeutic agents being dictated in part by genetic variants. Precision diagnoses and prognoses of individual patient responses rely on assessing known disease and immune markers before, during and/or after treatment. This proposal will interrogate the functional effects and druggablity of under- studied gene variants related to immune and drug response within the genome of individuals of African ancestry (AAs). Immune gene variants most common among AAs and predicted to be druggable will be engineered into cells lines of different geographical ancestry and evaluated for functional effects in vitro and/or in vivo and modeled in silico to predict structural changes to the wild type proteins and possible variant-drug interactions. Novel assays to screen for compounds with therapeutic potential will be developed and used for screening. Lead compound candidates will then be validated, optimized and tested in vitro and/or in vivo. This project has the potential to 1) establish ancestry-related host immunity as a contributing biological parameter of complex disease disparities; 2) fill in critical knowledge gaps by identifying novel players and mechanisms of inflammation and their role in complex disease; and, 3) possibly lead to the development of effective therapies to address health disparities.